This is a UIVII application to support the infrastructure of the original Nurses' Health Study (NHS). The NHS began in 1976 with 121,700 women, and has accumulated data from 19 questionnaires over 37 years; follow-up remains about 90 percent. The wealth of behavioral data combined with multiple bio-specimen collections, including blood, toenails, urine, buccal cells and tumor tissues beginning in 1.983 from a substantial proportion of women, provide an unparalleled resource in studying cancer prevention, etiology, and survival. Sustained follow-up of the NHS through repeated questionnaire mailings and continued identification of cancer incidence and mortality will permit critical new research. With the cohort's maturation (women are now 66+ years, at peak ages for cancer incidence), we propose to add emphasis to two overarching themes. First, we propose to expand the infrastructure for cancer survival research, including both the duration and quality of life in cancer patients. The many years of characterization of cancer patients before and after diagnosis, will allow us to distinguish between causes and consequences of cancer and its treatment. Second, we propose to improve our infrastructure to support a systems biology approach to our research, integrating questionnaire data with biomarkers in DNA, blood, tumor tissue, and other bio specimens; such research simultaneously integrating multiple systems, including behavior, genomics, transcriptomics, metabolomics, etc., may illuminate new mechanisms underlying cancer. Our large and growing number of incident cancer cases, and the unique combination of questionnaires and bio specimens, are a necessity for such integrative research. Specifically, our Aims include new collection of quality of life data, new (collection of tumor tissue (resulting in tissue collections, across 17 cancer sites), improved dat management/statistical support for big data analyses, and enhanced infrastructure for data sharing (the NHS resource is already extensively utilized - we have provided access to >75 external investigators in the past 5-6 years and 27 NCI cancer consortia). The NHS structure combines the long experience of senior leaders with support of several developing leaders; this combination is purposeful, to maintain leadership to sustain the cohort's future. In conclusion, NHS is well-positioned to continue cutting-edge research to reduce cancer morbidity and mortality. With the previous investment from NIH and investigators, the incremental costs of continuing this cohort are modest in relation to the uniquely valuable findings that will emerge in the coming 5 years. RELEVANCE: This UMI application is to extend follow-up of the original Nurses' Health Study, with extensive data on health, and lifestyle, integrated with biologic data (e.g., genomics, plasma biomarkers, tumor tissue, etc.), enabling novel research on cancer etiology, prevention and survival. No other cohort of comparable size includes such long follow-up with repeated behavioral measures, and bio specimens from 82,000 women. This enables studies of the time frame for causal and preventive factors for cancer etiology and survival.